Lymphangioleiomyomatosis. Insights about, and from, a Rare Disease. The report of Taveira-DaSilva and colleagues (1) in this issue. (pp. 1427â1431) brings ...
Editorials Lymphangioleiomyomatosis Insights about, and from, a Rare Disease The report of Taveira-DaSilva and colleagues (1) in this issue (pp. 1427–1431) brings the number of reports concerning lymphangioleiomyomatosis (LAM) published in the Journal over the last 3 years to nine (1–9). Given the rarity of this condition, this represents an exceptional rate of publication, reflecting substantial progress in our understanding of this disease. Many of these studies are part of a larger literature documenting advances in our knowledge of the molecular basis of tuberous sclerosis, which results from mutations of the tuberous sclerosis complex genes on chromosome 9 and 16. Collectively, the LAM reports tell an inspiring story of gene discovery (5, 9, 10), elucidation of a novel metastatic mechanism for LAM (2), and the dissection of molecular signaling pathways responsible for aberrant LAM cell growth and tissue remodeling (3, 11, 12). These studies have led to identification of promising molecular targets for therapy, which form the basis for pilot trials now underway in Europe and the United States. This latest addition to the literature on LAM might seem of little relevance to those who may never encounter patients with this condition. In addition to providing further characterization of a rare disease, however, the report serves more broadly to illustrate the utility of exercise testing in any chronic disease. One objective of such testing, of course, is to identify how the disease affects exercise function. In this respect, the report reinforces and extends the results of a previous, smaller series (13), including the observation that LAM can induce abnormalities of exercise responses characteristic of obstructive lung disease, or alternatively, of interstitial diseases. In keeping with the clinical heterogeneity of LAM, which may be dominated by airflow obstruction or interstitial infiltration, no single exercise abnormality was uniquely characteristic of the entire group. Importantly, findings of clinical importance to individual patients, such as arterial oxygen desaturation, were sometimes unexpected. Another goal of exercise testing is to quantify functional capacity, or conversely, impairment. Maximum oxygen uptake, the gold standard measure of exercise capacity, is also the most widely accepted variable for quantifying exercise impairment in disease. Being dependent on the integrated responses of multiple organs, maximal oxygen uptake captures the net effect of diverse functional defects and compensatory mechanisms on the cardiovascularrespiratory-muscular axis of oxygen delivery and utilization. Consistent with this, Taveira-DaSilva and colleagues found that among their patients, FEV1 and diffusing capacity together predicted exercise capacity better than either variable alone. Despite considering multiple clinical and laboratory variables, however, a multivariate model was only modestly predictive of the measured maximal oxygen uptake. This may in part reflect methodologic limitations, including some variability in approaches to testing and omission of some potentially relevant variables. It is unlikely, however, that more rigorously standardized methods or more exhaustive analysis would substantially alter the study’s findings. A sampling of the many similar analyses of patients with chronic
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obstructive lung disease (14–16) variously identify lung mechanics, diffusing capacity, and skeletal muscle as determinants of impairment in this population. In the end, however, exercise capacity is never found to be adequately predicted from resting measures, and exercise measurements are needed to truly quantify exercise impairment. But are quantitative measures of exercise impairment important? Despite evidence that laboratory measures of exercise capacity are highly related to functionality in daily life (17), there are as yet only selected circumstances in which exercise testing has been incorporated into recommendations for medical management of individual patients. For the evaluation of the effectiveness of new drugs or interventions, in contrast, objective measures of exercise capacity have wide and increasing applications. Exercise testing has proven tolerable enough, and the data robust enough, to identify functional improvements related to interventions in such diverse and complex populations as heart failure, chronic obstructive lung disease, pulmonary hypertension, and end-stage renal disease, among others. In this context, the study of Taveira-DaSilva and colleagues is particularly timely (1). As new insights into the pathogenesis of LAM identify the possibility of novel interventions, carefully executed physiologic studies will be critical for the design of trials that assess the effectiveness of these therapeutic strategies. A third goal of exercise testing is for estimating prognosis. It is well established that exercise capacity predicts mortality in a variety of chronic diseases. The most pragmatic application of this observation has been the use of maximal oxygen uptake as a criterion for heart transplantation (18), where optimal organ allocation and individual patient’s interests both require objective assessment of near-term mortality risk. Recent observations (19) regarding the effect of -blocker therapy on the relationship between exercise capacity and mortality in heart failure raise the caution that population-specific calibration of this relationship is needed if it is to be used in clinical decision-making. Exercise capacity also appears to predict mortality in chronic obstructive pulmonary disease (20), though fewer data of this kind are available for other forms of lung disease. The cross-sectional analysis of Taveira-DaSilva and colleagues (1) cannot define the prognostic value of exercise capacity in LAM, and assessment at one point in time may provide incomplete prognostic information in this condition due to its variable rate of progression. Longitudinal follow-up of this and other populations with chronic lung diseases will be essential to determine how such information can contribute to complex decision-making concerning lung transplantation or other high-risk interventions. The very existence of the data set represented in this report is remarkable. The 294 patients who volunteered for this study represent approximately 60% of all LAM patients that have been identified by the LAM Foundation in the United States. Such a level of participation is only possible when patients recognize the value of research and encourage one another to enroll in critical studies. LAM patients from around the world also contributed to the other recent reports published in the Journal, by their donation of monies for Foundation and federally funded research, tissue, and time. Rare lung disease populations of all types can take heart from the scientific trajectory that results from synergistic interactions between investigators and engaged patient advocacy groups.
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Conflict of Interest Statement : K.S. has served as a paid consultant to various pharmaceutical companies on the design of exercise testing for use in clinical trails. F.M. has no relationship with commercial firms to declare. He is a coinvestigator for a trial of rapamcyin in patients with tuberous sclerosis and LAM, which is funded by the Tuberous Sclerosis alliance, the LAM Foundation, and the National Cancer Institute. Wyeth is providing the drug but no other funds. He is Scientific Director of the LAM Foundation, which is a volunteer position. Some of the LAM conferences that he has chaired are sponsored by pharmaceutical firms including Wyeth and Home Products.
Kathy E. Sietsema, M.D. Harbor UCLA Medical Center Torrance, California Francis X. McCormack, M.D. University of Cincinnati Cincinnati, Ohio
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References 1. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, Kristof AS, Avila NA, Rabel A, Travis WD, Moss J. Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2003;168:1427–1431. 2. Karbowniczek M, Astrinidis A, Balsara BR, Testa JR, Lium JH, Colby TV, McCormack FX, Henske EP. Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med 2003;167:976–982. 3. Inoue Y, King TE Jr, Barker E, Daniloff E, Newman LS. Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis. Am J Respir Crit Care Med 2002;166: 765–773. 4. Kumaki F, Takeda K, Yu ZX, Moss J, Ferrans VJ. Expression of human telomerase reverse transcriptase in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2002;166:187–191. 5. Yu J, Astrinidis A, Henske EP. Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis. Am J Respir Crit Care Med 2001;164:1537–1540. 6. Taveira-DaSilva AM, Hedin C, Stylianou MP, Travis WD, Matsui K, Ferrans VJ, Moss J. Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2001;164:1072–1076. 7. Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack FX. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 2001;164:661–668. 8. Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks PG, Hedin CJ, Hunsberger S, Kristof AS. Prevalence and clinical character-
14.
15.
16.
17.
18.
19.
20.
istics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001;164:669–671. Strizheva GD, Carsillo T, Kruger WD, Sullivan EJ, Ryu JH, Henske EP. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am J Respir Crit Care Med 2001; 163:253–258. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000;97:6085–6090. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM, et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002;277: 30958–30967. Krymskaya VP. Tumour suppressors hamartin and tuberin: intracellular signalling. Cell Signal 2003;15:729–739. Crausman RS, Jennings CA, Mortenson RL, Ackerson LM, Irvin CG, King TE Jr. Lymphangioleiomyomatosis: the pathophysiology of diminished exercise capacity. Am J Respir Crit Care Med 1996;153: 1368–1376. Kobayashi A, Yoneda T, Yoshikawa M, Ikuno M, Takenaka H, Fukuoka A, Narita N, Nezu K. The relation of fat-free mass to maximum exercise performance in patients with chronic obstructive pulmonary disease. Lung 2000;178:119–127. Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic-Emil J, Lisboa C. Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest. Eur Respir J 2000;16:269–275. Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996;153:976–980. Morey MC, Pieper CF, Cornoni-Huntley J. Is there a threshold between peak oxygen uptake and self-reported physical functioning in older adults? Med Sci Sports Exerc 1998;30:1223–1229. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83:778–786. Peterson LR, Schechtman KB, Ewald GA, Geltman EM, Meyer T, Krekeler P, Rogers JG. The effect of beta-adrenergic blockers on the prognostic value of peak exercise oxygen uptake in patients with heart failure. J Heart Lung Transplant 2003;22:70–77. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med 2003;167:544–549.
DOI: 10.1164/rccm.2310006
Noninvasive Ventilation for Cardiogenic Pulmonary Edema Froth and Bubbles? Acute cardiogenic pulmonary edema usually presents with the sudden onset of acute hypoxemic respiratory failure that requires rapid assessment and treatment. Although this may be secondary to sudden decompensation of chronic heart failure, myocardial ischemia is also common. Typically, patients are hypoxemic with increased work of breathing, acidemic because of both respiratory and metabolic factors (1), and hypertensive and tachycardic. Diastolic dysfunction is the major contributor to raised hydrostatic pressure and pulmonary edema (2). Despite standard medical therapy with oxygen, nitrates, and diuretics, ventilator assistance may be needed. Noninvasive ventilation is widely used in cardiogenic pulmonary edema (3, 4), usually resulting in rapid relief of dyspnea. Although this simple but dramatic clinical observation was made many years ago (5), there are many unanswered questions. In
this issue of the Journal (pp. 1432–1437), Nava and coworkers (6) report important findings from a multicenter study that helps focus some of these issues. While the term noninvasive ventilation covers numerous methods of ventilator assistance without endotracheal intubation, it is most commonly applied as positive airway pressure using a mask as the interface. The simplest and most commonly used technique in cardiogenic pulmonary edema is continuous positive airway pressure (CPAP). There has been growing interest, however, in the use of modes where inspiratory effort is supported by a greater level of positive pressure (pressure support) interposed on top of positive end-expiratory pressure (PEEP), also termed bilevel positive airway pressure. Raised intrathoracic pressure increases functional residual capacity and oxygenation, improves lung mechanics, and reduces work of
